Skip to main content
Log in

Plasma metabolomics reveals the intervention mechanism of different types of exercise on chronic unpredictable mild stress-induced depression rat model

  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Objective

To study the effects of different types of exercise on the plasma metabolomics of chronic unpredictable mild stress (CUMS)-induced depressed rats based on 1H-NMR metabolomics techniques, and to explore the potential mechanisms of exercise for the treatment of depression. Rats were randomly divided into blank control group (C), CUMS control group (D), pre-exercise with CUMS group (P), CUMS with aerobic exercise group, CUMS with resistance exercise group (R), and CUMS with aerobic + resistance exercise group (E). The corresponding protocol intervention was applied to each group of rats. Body weight, sucrose preference and open field tests were performed weekly during the experiment to evaluate the extent of depression in rats. Plasma samples from each group of rats were collected at the end of the experiment, and then the plasma was analyzed by 1H-NMR metabolomics combined with multivariate statistical analysis methods to identify differential metabolites and perform metabolic pathway analysis. (1) Compared with the group D, the body weight, sucrose preference rate, and the number of crossings and standings in the different types of exercise groups were significantly improved (p < 0.05 or p < 0.01). (2) Compared to group C, a total of 15 differential metabolites associated with depression were screened in the plasma of rats in group D, involving 6 metabolic pathways. Group P can regulate the levels of 6 metabolites: valine, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. Group A can regulate the levels of 6 metabolites: N-acetylglycoprotein, leucine, lactate, low density lipoprotein, glucose and acetoacetic acid. Group R can regulate the levels of 6 metabolites: choline, lactate, inositol, glucose, phosphocreatine and acetoacetic acid. Group E can regulate the levels of 5 metabolites: choline, citric acid, glucose, acetone and acetoacetic acid. The different types of exercise groups can improve the depressive symptoms in CUMS rats, and there are common metabolites and metabolic pathways for their mechanism of effects. This study provides a powerful analytical tool to study the mechanism of the antidepressant effect of exercise, and provides an important method and basis for the early diagnosis, prevention and treatment of depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

Code availability

Not applicable

References

  • COVID-19 Mental Disorders Collaborators (2021) Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet (London, England) 398:1700–1712

  • Ament W, Verkerke GJ (2009) Exercise and fatigue. Sports medicine (Auckland, N.Z.). 39, 389-422

  • Antoniuk S, Bijata M, Ponimaskin E, Wlodarczyk J (2019) Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability. Neurosci Biobehav Rev 99:101–116

  • Baranyi A, Amouzadeh-Ghadikolai O, von Lewinski D, Rothenhäusler HB, Theokas S, Robier C, Mangge H, Reicht G, Hlade P, Meinitzer A (2016) Branched-Chain Amino Acids as New Biomarkers of Major Depression - A Novel Neurobiology of Mood Disorder. PLoS One 11:e0160542

    Article  PubMed  PubMed Central  Google Scholar 

  • Blomstrand E (2006) A role for branched-chain amino acids in reducing central fatigue. J Nutr 136:544s–547s

    Article  CAS  PubMed  Google Scholar 

  • Brietzke E, Mansur RB, Subramaniapillai M, Balanzá-Martínez V, Vinberg M, González-Pinto A, Rosenblat JD, Ho R, McIntyre RS (2018) Ketogenic diet as a metabolic therapy for mood disorders: Evidence and developments. Neurosci Biobehav Rev 94:11–16

    Article  CAS  PubMed  Google Scholar 

  • Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, Fang YY, Zhang J, Li SJ, Xiong WC, Yan HC, Gao YB, Liu JH, Li XW, Sun LR, Zeng YN, Zhu XH, Gao TM (2013) Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med 19:773–777

    Article  CAS  PubMed  Google Scholar 

  • Chiappelli J, Rowland LM, Wijtenburg SA, Muellerklein F, Tagamets M, McMahon RP, Gaston F, Kochunov P, Hong LE (2015) Evaluation of Myo-Inositol as a Potential Biomarker for Depression in Schizophrenia. Neuropsychopharmacol Official Public Am College Neuropsychopharmacol 40:2157–2164

    Article  CAS  Google Scholar 

  • De Castro F, Benedetti M, Del Coco L, Fanizzi FP (2019) NMR-Based Metabolomics in Metal-Based Drug Research. Molecules (Basel, Switzerland). 24

  • Delcourt N, Claudepierre T, Maignien T, Arnich N, Mattei C (2017) Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy. Toxins. 10

  • Diepenbroek C, Serlie MJ, Fliers E, Kalsbeek A, la Fleur SE (2013) Brain areas and pathways in the regulation of glucose metabolism. BioFactors (Oxford, England) 39:505–513

    Article  CAS  PubMed  Google Scholar 

  • Du Y, Wei J, Zhang Z, Yang X, Wang M, Wang Y, Qi X, Zhao L, Tian Y, Guo W, Wang Q, Deng W, Li M, Lin D, Li T, Ma X (2021) Plasma Metabolomics Profiling of Metabolic Pathways Affected by Major Depressive Disorder. Front Psychiatry 12:644555

    Article  PubMed  PubMed Central  Google Scholar 

  • Evans M, Cogan KE, Egan B (2017) Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol 595:2857–2871

    Article  CAS  PubMed  Google Scholar 

  • Feng YS, Yang SD, Tan ZX, Wang MM, Xing Y, Dong F, Zhang F (2020) The benefits and mechanisms of exercise training for Parkinson's disease. Life Sci 245:117345

    Article  CAS  PubMed  Google Scholar 

  • Fu M, Bao T, Yu H (2022) Metabolomics investigation on antiobesity effects of Corydalis bungeana on high-fat high-sugar diet-induced obese rats. 14, 414-421

  • Hao Y, Ge H, Sun M, Gao Y (2019) Selecting an Appropriate Animal Model of Depression. International journal of molecular sciences. 20

  • Johnson CH, Ivanisevic J, Siuzdak G (2016) Metabolomics: beyond biomarkers and towards mechanisms. Nature reviews. Mol Cell Biol 17:451–459

    CAS  Google Scholar 

  • Kandola A, Ashdown-Franks G, Hendrikse J, Sabiston CM, Stubbs B (2019) Physical activity and depression: Towards understanding the antidepressant mechanisms of physical activity. Neurosci Biobehav Rev 107:525–539

    Article  PubMed  Google Scholar 

  • Lee TH, Kim K, Shin MS, Kim CJ, Lim BV (2015) Treadmill exercise alleviates chronic mild stress-induced depression in rats. J Exercise Eehab 11:303–310

    CAS  Google Scholar 

  • Li H, Xiang Y, Zhu Z, Wang W, Jiang Z, Zhao M, Cheng S, Pan F, Liu D, Ho RCM, Ho CSH (2021) Rifaximin-mediated gut microbiota regulation modulates the function of microglia and protects against CUMS-induced depression-like behaviors in adolescent rat. J Neuroinflammation 18:254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu CC, Wu YF, Feng GM, Gao XX, Zhou YZ, Hou WJ, Qin XM, Du GH, Tian JS (2015) Plasma-metabolite-biomarkers for the therapeutic response in depressed patients by the traditional Chinese medicine formula Xiaoyaosan: A (1)H NMR-based metabolomics approach. J Affect Disord 185:156–163

    Article  CAS  PubMed  Google Scholar 

  • Liu MY, Yin CY, Zhu LJ, Zhu XH, Xu C, Luo CX, Chen H, Zhu DY, Zhou QG (2018a) Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat Protoc 13:1686–1698

    Article  CAS  PubMed  Google Scholar 

  • Liu W, Xue X, Xia J, Liu J, Qi Z (2018b) Swimming exercise reverses CUMS-induced changes in depression-like behaviors and hippocampal plasticity-related proteins. J Affect Disord 227:126–135

    Article  PubMed  Google Scholar 

  • Liu X, Zhao W, Hu F, Hao Q, Hou L, Sun X, Zhang G, Yue J, Dong B (2022) Comorbid anxiety and depression, depression, and anxiety in comparison in multi-ethnic community of west China: prevalence, metabolic profile, and related factors. J Affect Disord 298:381–387

    Article  PubMed  Google Scholar 

  • Malhi GS, Mann JJ (2018) Depression. Lancet (London, England). 392, 2299-2312

  • Marwaha S, Palmer E, Suppes T, Cons E, Young AH, Upthegrove R (2023) Novel and emerging treatments for major depression. Lancet (London, England) 401:141–153

    Article  CAS  PubMed  Google Scholar 

  • Memon AA, Coleman JJ, Amara AW (2020) Effects of exercise on sleep in neurodegenerative disease. Neurobiol Dis 140:104859

    Article  PubMed  PubMed Central  Google Scholar 

  • Moraes HS, Silveira HS, Oliveira NA, Matta Mello Portugal E, Araújo NB, Vasques PE, Bergland A, Santos TM, Engedal K, Coutinho ES, Schuch FB, Laks J, Deslandes AC (2020) Is Strength Training as Effective as Aerobic Training for Depression in Older Adults? A Randomized Controlled Trial. Neuropsychobiology 79:141–149

    Article  PubMed  Google Scholar 

  • Nedic Erjavec G, Sagud M, Nikolac Perkovic M, Svob Strac D, Konjevod M, Tudor L, Uzun S, Pivac N (2021) Depression: Biological markers and treatment. Prog Neuro-Psychopharmacol Biol Psychiatry 105:110139

    Article  CAS  Google Scholar 

  • Okuyama T, Akechi T, Mackenzie L, Furukawa TA (2017) Psychotherapy for depression among advanced, incurable cancer patients: A systematic review and meta-analysis. Cancer Treat Rev 56:16–27

    Article  PubMed  Google Scholar 

  • Özbeyli D, Sarı G, Özkan N, Karademir B, Yüksel M, Çilingir Kaya ÖT, Kasımay Çakır Ö (2017) Protective effects of different exercise modalities in an Alzheimer's disease-like model. Behav Brain Res 328:159–177

    Article  PubMed  Google Scholar 

  • Patel S, Sharma D, Uniyal A, Akhilesh, Gadepalli A, Tiwari V (2022) Recent advancements in biomarker research in schizophrenia: mapping the road from bench to bedside. Metab Brain Dis 37:2197–2211

    Article  CAS  PubMed  Google Scholar 

  • Peng GJ, Tian JS, Gao XX, Zhou YZ, Qin XM (2015) Research on the Pathological Mechanism and Drug Treatment Mechanism of Depression. Curr Neuropharmacol 13:514–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Price RB, Duman R (2020) Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry 25:530–543

    Article  PubMed  Google Scholar 

  • Pu J, Liu Y, Gui S, Tian L, Yu Y, Song X, Zhong X, Chen X, Chen W, Zheng P, Zhang H, Gong X, Liu L, Wu J, Wang H, Xie P (2021a) Metabolomic changes in animal models of depression: a systematic analysis. Mol Psychiatry 26:7328–7336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pu J, Liu Y, Zhang H, Tian L, Gui S, Yu Y, Chen X, Chen Y, Yang L, Ran Y, Zhong X, Xu S, Song X, Liu L, Zheng P, Wang H, Xie P (2021b) An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder. Mol Psychiatry 26:4265–4276

    Article  CAS  PubMed  Google Scholar 

  • Rabinowitz JD, Enerbäck S (2020) Lactate: the ugly duckling of energy metabolism. Nature Metab 2:566–571

    Article  CAS  Google Scholar 

  • Rodrigues MF, Stotzer US, Domingos MM, Deminice R, Shiguemoto GE, Tomaz LM, Sousa NM, Ferreira FC, Leite RD, Selistre-de-Araújo HS, Jordão-Júnior AA, Baldissera V, Perez SE (2013) Effects of ovariectomy and resistance training on oxidative stress markers in the rat liver. Clinics (Sao Paulo, Brazil) 68:1247–1254

    Article  PubMed  Google Scholar 

  • Sarter M, Parikh V (2005) Choline transporters, cholinergic transmission and cognition. Nature reviews. Neuroscience 6:48–56

    CAS  PubMed  Google Scholar 

  • Scheffer DDL, Latini A (2020) Exercise-induced immune system response: Anti-inflammatory status on peripheral and central organs. Biochimica et biophysica acta. Mol Basis Disease 1866:165823

    Article  CAS  Google Scholar 

  • Schuch FB, Vancampfort D, Richards J, Rosenbaum S, Ward PB, Stubbs B (2016) Exercise as a treatment for depression: A meta-analysis adjusting for publication bias. J Psychiatr Res 77:42–51

    Article  PubMed  Google Scholar 

  • Setoyama D, Kato TA, Hashimoto R, Kunugi H, Hattori K, Hayakawa K, Sato-Kasai M, Shimokawa N, Kaneko S, Yoshida S, Goto YI, Yasuda Y, Yamamori H, Ohgidani M, Sagata N, Miura D, Kang D, Kanba S (2016) Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis. PLoS One 11:e0165267

    Article  PubMed  PubMed Central  Google Scholar 

  • Shankman SA, Gorka SM, Katz AC, Klein DN, Markowitz JC, Arnow BA, Manber R, Rothbaum BO, Thase ME, Schatzberg AF, Keller MB, Trivedi MH, Kocsis JH (2017) Side Effects to Antidepressant Treatment in Patients With Depression and Comorbid Panic Disorder. J Clin Psychiatry 78:433–440

    Article  PubMed  Google Scholar 

  • Slade SC, Keating JL (2012) Exercise prescription: a case for standardised reporting. Br J Sports Med 46:1110–1113

    Article  PubMed  Google Scholar 

  • Sobieraj DM, Martinez BK, Hernandez AV, Coleman CI, Ross JS, Berg KM, Steffens DC, Baker WL (2019) Adverse Effects of Pharmacologic Treatments of Major Depression in Older Adults. J Am Geriatr Soc 67:1571–1581

    Article  PubMed  Google Scholar 

  • Sperringer JE, Addington A, Hutson SM (2017) Branched-Chain Amino Acids and Brain Metabolism. Neurochem Res 42:1697–1709

    Article  CAS  PubMed  Google Scholar 

  • Stollar EJ, Smith DP (2020) Uncovering protein structure. Essays Biochem 64:649–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suneson K, Lindahl J, Chamli Hårsmar S, Söderberg G, Lindqvist D (2021) Inflammatory Depression-Mechanisms and Non-Pharmacological Interventions. Int J Mol Sci 22(4):1640

  • Tang BL (2020) Glucose, glycolysis, and neurodegenerative diseases. J Cell Physiol 235:7653–7662

    Article  CAS  PubMed  Google Scholar 

  • Taylor MJ, Wilder H, Bhagwagar Z, Geddes J (2004) Inositol for depressive disorders. Cochrane Database Syst Rev 2004(2):CD004049

  • Yuan W, Zhang J, Li S, Edwards JL (2011) Amine metabolomics of hyperglycemic endothelial cells using capillary LC-MS with isobaric tagging. J Proteome Res 10:5242–5250

    Article  CAS  PubMed  Google Scholar 

  • Zalachoras I, Hollis F, Ramos-Fernández E, Trovo L, Sonnay S, Geiser E, Preitner N, Steiner P, Sandi C, Morató L (2020) Therapeutic potential of glutathione-enhancers in stress-related psychopathologies. Neurosci Biobehav Rev 114:134–155

    Article  CAS  PubMed  Google Scholar 

  • Zheng P, Gao HC, Li Q, Shao WH, Zhang ML, Cheng K, Yang DY, Fan SH, Chen L, Fang L, Xie P (2012) Plasma metabonomics as a novel diagnostic approach for major depressive disorder. J Proteome Res 11:1741–1748

    Article  CAS  PubMed  Google Scholar 

  • Zhou X, Liu L, Lan X, Cohen D, Zhang Y, Ravindran AV, Yuan S, Zheng P, Coghill D, Yang L, Hetrick SE, Jiang X, Benoliel JJ, Cipriani A, Xie P (2019) Polyunsaturated fatty acids metabolism, purine metabolism and inosine as potential independent diagnostic biomarkers for major depressive disorder in children and adolescents. Mol Psychiatry 24:1478–1488

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Project of Natural Science Research in Shanxi Province, China (202103021224027).

Author information

Authors and Affiliations

Authors

Contributions

Y.H., B.Z., X.L., and J.T. conceived and supervised the study; B.Z., and X.L. performed the experiments; B.Z., and X.L. analyzed the data and drafted the manuscript; S.Z. reviewed and edited the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Xiangyu Liu.

Ethics declarations

Competing interests

All authors declare that they have no competing interests.

Ethics approval

The experimental protocol was approved by the Scientific Research Ethics Committee of Shanxi University (SXULL-20200069)

Consent to participate

Not applicable

Consent for publication

Not applicable

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(PDF 232 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Zhang, B., Tian, J. et al. Plasma metabolomics reveals the intervention mechanism of different types of exercise on chronic unpredictable mild stress-induced depression rat model. Metab Brain Dis 39, 1–13 (2024). https://doi.org/10.1007/s11011-023-01310-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-023-01310-7

Keywords

Navigation